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4j0p

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{{STRUCTURE_4j0p| PDB=4j0p | SCENE= }}
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==CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide==
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===CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide===
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<StructureSection load='4j0p' size='340' side='right' caption='[[4j0p]], [[Resolution|resolution]] 1.97&Aring;' scene=''>
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{{ABSTRACT_PUBMED_23590342}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4j0p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J0P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J0P FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1H8:N-{3-[(4S)-2-AMINO-4-METHYL-5,6-DIHYDRO-4H-1,3-OXAZIN-4-YL]-4-FLUOROPHENYL}-5-CYANOPYRIDINE-2-CARBOXAMIDE'>1H8</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4j0t|4j0t]], [[4j0v|4j0v]], [[4j0y|4j0y]], [[4j0z|4j0z]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4j0p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j0p OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4j0p RCSB], [http://www.ebi.ac.uk/pdbsum/4j0p PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the pKa and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Abeta40 &amp; 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Abeta40 &amp; 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.
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==Function==
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beta-Secretase (BACE1) Inhibitors with High In Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer's Disease.,Hilpert H, Guba W, Woltering TJ, Wostl W, Pinard E, Mauser H, Mayweg AV, Rogers-Evans M, Humm R, Krummenacher D, Muser T, Schnider C, Jacobsen H, Ozmen L, Bergadano A, Banner DW, Hochstrasser R, Kuglstatter A, David-Pierson P, Fischer H, Polara A, Narquizian R J Med Chem. 2013 Apr 16. PMID:23590342<ref>PMID:23590342</ref>
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[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4j0p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J0P OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:023590342</ref><references group="xtra"/><references/>
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*[[Beta secretase|Beta secretase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]
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[[Category: Kuglstatter, A.]]
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[[Category: Kuglstatter, A]]
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[[Category: Stihle, M.]]
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[[Category: Stihle, M]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Protease inhibitor]]
[[Category: Protease inhibitor]]

Revision as of 16:40, 21 December 2014

CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH 5-Cyano-pyridine-2-carboxylic acid [3-((S)-2-amino-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide

4j0p, resolution 1.97Å

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